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Magnitude of Effects on Health Outcomes: A relative risk (RR) reduction of about 50% overall with a dose response ranging from 5% to 10% RR reduction per year of use to maximum RR reductions of up to 80%.

External Validity: Good.

Oral Contraceptives: Harms

Based on solid evidence, combined current use of estrogen/progestogen oral contraceptive use is associated with an increased risk of venous thromboembolism. Oral contraceptives are not associated with a long-term increased risk of breast cancer but may be associated with a short-term increased risk while a woman is taking oral contraceptives. The risk of breast cancer declines with time since last use.

Description of the Evidence

Study Design: Evidence obtained from observational studies.

Internal Validity: Good.

Consistency: Good.

Magnitude of Effects on Health Outcomes: The risks may vary by preparation. Overall, the absolute risk of venous thromboembolism is about three events per 10,000 women per year while taking oral contraceptives. The risk is increased by smoking. Breast cancer risk among long-term (>10 years) current users is estimated at one extra case per year per 100,000 women. The risk dissipates with time since last use.

External Validity: Good.

Prophylactic Oophorectomy: Benefits

Based on solid evidence, prophylactic bilateral oophorectomy is associated with a decreased risk of ovarian cancer. Peritoneal carcinomatosis has been reported following prophylactic removal of the ovaries. Prophylactic oophorectomy, along with salpingo-oophorectomy, is generally reserved for women at high risk of developing ovarian cancer, such as women who have a deleterious mutation in a BRCA1 or BRCA2 gene.

Magnitude of Effects on Health Outcomes: 90% reduction in risk of ovarian cancer observed among women with a BRCA1 or BRCA2 mutation.

External Validity: Good.

Prophylactic Oophorectomy: Harms

Based on solid evidence, prophylactic oophorectomy among women who are still menstruating at the time of surgery is associated with infertility, vasomotor symptoms, decreased sexual interest, vaginal dryness, urinary frequency, decreased bone mineral density, and increased cardiovascular disease.

Description of the Evidence

Study Design: Cohort and case-control studies.

Internal Validity: Good.

Consistency: Good.

Magnitude of Effects on Health Outcomes: Reported prevalence of vasomotor symptoms varies from 41% to 61.4% among women who underwent oophorectomy prior to natural menopause. Women with bilateral oophorectomy who did not take hormone therapy were twice as likely to have moderate or severe hot flashes compared to women undergoing a natural menopause. The RR of cardiovascular disease among women with bilateral oophorectomy and early menopause was 4.55 (95% confidence interval, 2.56–9.01).

External Validity: Good.

Significance

Incidence and Mortality

In 2014, it is estimated that 21,980 new cases of ovarian cancer will be diagnosed and 14,270 deaths due to ovarian cancer will occur. Incidence rates have been relatively stable since 1992. Death rates for ovarian cancer decreased by 2.8% per year from 2006 to 2010.[1]

For the general population of women, the lifetime risk of developing ovarian cancer is 1.39%; the lifetime risk of dying from ovarian cancer is 1.04%.[2] Some women are at an increased risk due to an inherited susceptibility to ovarian cancer with the magnitude of that risk depending on the affected gene and specific mutation. Underlying ovarian cancer risk can be assessed through accurate pedigrees and/or genetic markers of risk. Because of uncertainties about cancer risks associated with specific gene mutations, genetic information may be difficult to interpret outside of families with a high incidence of ovarian cancer. Three inherited ovarian cancer susceptibility syndromes have been described: (1) familial site-specific ovarian cancer; (2) familial breast/ovarian cancer; and (3) Lynch II syndrome, which is a combination of breast, ovarian, endometrial, gastrointestinal, and genitourinary cancers.[3,4] Considering family history in the absence of specific information on BRCA1/2 mutation status, unaffected women who have two or three relatives with ovarian cancer have a cumulative ovarian cancer risk of about 7%.[3,5] Women who have a mother or sister with ovarian cancer have a cumulative lifetime risk of ovarian cancer of about 5%.

This summary does not address the groups that are at high risk due to inherited genetic factors. (Refer to the PDQ summary on the Genetics of Breast and Ovarian Cancer for more information.)

Evidence of Benefit

Pathogenesis

The pathogenesis of ovarian carcinoma remains unclear. Several theories have been proposed to explain the epidemiology of ovarian cancer including the theory of "incessant ovulation,"[1,2] gonadotropin stimulation,[3] excess androgenic stimulation,[4] and inflammation.[5] Associated risk factors for ovarian cancer support some or all of these hypotheses. Oral contraceptive use is consistently associated with a decreased risk of ovarian cancer and may operate through preventing the trauma from repeated ovulation by lowering exposure to gonadotropins. No one theory, however, explains all the associated risk factors.

Protective Factors

Factors associated with a decreased risk of ovarian cancer include: (1) using oral contraceptives, (2) having and breastfeeding children, (3) having a bilateral tubal ligation or hysterectomy, and (4) having a prophylactic oophorectomy.

Oral contraceptives

Multiple studies have consistently demonstrated a decrease in ovarian cancer risk in women who take oral contraceptives.[6,7] The protective association increases with the duration of oral contraceptive use and persists up to 25 years after discontinuing oral contraceptives. A review of the literature demonstrated a 10% to 12% decrease in risk associated with use for 1 year and an approximate 50% decrease after 5 years of use. This reduced risk was present among both nulliparous and parous women.[6] A protective association between oral contraceptives and risk of ovarian cancer has been observed in most studies [8,9,10] among women who carry a mutation in BRCA1 and BRCA2 genes. A population-based study conducted in Israel did not observe an association between oral contraceptives and ovarian cancer, but parity was protective.[11]

Tubal sterilization

In a prospective study, a 33% decrease in the risk of ovarian cancer among women who underwent tubal sterilization was observed after adjusting the data for oral contraceptive use, parity, and other ovarian cancer risk factors. This study also demonstrated a weaker, although statistically significant, decrease in risk associated with simple hysterectomy.[12]

Prophylactic oophorectomy

Prophylactic oophorectomy may reduce the risk of developing ovarian cancer for women at high risk. One group for whom this option is considered is women who have an inherited susceptibility to ovarian cancer such as women who have mutations in BRCA1, BRCA2, or hereditary nonpolyposis colon cancer (HNPCC)–associated genes. These women have a lifetime risk much higher than the general population, in the range of 20% to 60%. Evidence of the magnitude of risk reduction associated with bilateral oophorectomy comes primarily from studies of women with an inherited risk of cancer. A family-based study among women with BRCA1 or BRCA2 mutations found that of the 259 women who had undergone bilateral prophylactic oophorectomy, 2 (0.8%) developed subsequent papillary serous peritoneal carcinoma and 6 (2.8%) had stage I ovarian cancer at the time of surgery. Twenty-percent of the 292 matched controls who did not have prophylactic surgery developed ovarian cancer. Prophylactic surgery was associated with a greater than 90% reduction in the risk of ovarian cancer, (relative risk [RR] = 0.04; 95% confidence interval [CI], 0.01–0.16) with an average follow-up of 9 years;[13] however, family-based studies may be associated with biases due to case selection and other factors that may influence the estimate of benefit.[14] A study of 315 women with documented HNPCC–associated germline mutations found no ovarian cancer among 47 women who had bilateral salpingo-oophorectomy and 12 cases (5%) among women with mutations who had not had surgery for a prevented fraction of 100% (95% CI, 62%–100%). Prophylactic surgery, however, is not 100% effective. Case reports and case series have reported the occurrence of peritoneal carcinomatosis following oophorectomy.[15,16,17]

The degree of risk of ovarian cancer, potential morbidity and mortality of surgery, and the risks associated with early menopause, should be taken into account when considering prophylactic oophorectomy for high-risk women. Adverse effects of bilateral oophorectomy and premature menopause include infertility, vasomotor symptoms, decline in sexual interest and activity, cardiovascular disease, and osteoporosis. Among women who have not taken hormone therapy, women undergoing bilateral oophorecotmy were twice as likely to have moderate or severe hot flashes than women who underwent natural menopause (odds ratio [OR] = 2.44; 95% CI, 1.03–5.77).[18] Women at increased hereditary risk of ovarian cancer who underwent oophorectomy without hormone therapy reported statistically significantly more vasomotor symptoms than women choosing screening or those using hormone replacement therapy (HRT).[19] These women also reported lower sexual function scores but the difference was not statistically significant.[19] A meta-analysis of early menopause as a risk factor for cardiovascular disease observed a pooled risk of 4.55 (95% CI, 2.56–8.01) among women with bilateral oophorectomy and early menopause (defined as younger than 50 years).[20] Early menopause is also associated with an increased risk of fracture (OR = 1.5; 95% CI, 1.2–1.8).[21]

Nonhereditary Factors Associated With an Increased Risk of Ovarian Cancer

Hormone replacement therapy/hormone therapy

Postmenopausal use of HRT, also called hormone therapy (HT), is associated with an increased risk of developing ovarian cancer.[22,23,24] The risk may vary by use of estrogen replacement therapy (ERT), also called estrogen therapy (ET), or estrogen-progestin replacement therapy (EPRT). A cohort study of women who participated in the Breast Cancer Detection Demonstration Project showed an increased risk of ovarian cancer associated with use of ERT/ET and ERT/ET followed by EPRT. A RR of 3.2 (95% CI, 1.7–5.7) was associated with 20 or more years use of ERT/ET only, with a statistically significant trend of increasing risk with increasing duration of use. Although no risk of ovarian cancer associated with EPRT use alone was observed, the number of women in this subgroup was small and an associated risk cannot be ruled out.[23] A case-control study of ovarian cancer also did not find an association between combined estrogen and progestin, but use of estrogen-only therapy for more than 10 years was associated with an increased risk.[25] An association between postmenopausal estrogen use and ovarian cancer mortality also has been shown. Vital status of 211,581 postmenopausal women, all of whom completed a baseline questionnaire in 1982 documenting no history of cancer, hysterectomy, or ovarian surgery was assessed through December 31, 1996. Women who were using estrogen at baseline had a significantly higher risk of ovarian cancer death than women who never used estrogen (RR = 1.51; 95% CI, 1.16–1.96). The risk increased with longer duration of use; women using estrogen at baseline and those who had used estrogen for at least 10 years had a higher risk of ovarian cancer death than did women who had never used estrogen, respectively (RR = 2.20; 95% CI, 1.53–3.17).[26]

The largest double-blind randomized controlled trial of combined HRT/HT was the Women's Health Initiative (N = 16,608). This study found that, after an average follow-up of 5.6 years, women taking combined HRT/HT (compared with women randomly assigned to placebo) had a nonstatistically significant increased risk of invasive ovarian cancer (hazard ratio [HR] = 1.58; 0.77–3.24), with a wide confidence interval.[27]

Infertility treatment

A collaborative analysis of case-control studies, analyzing data from 2,200 women with ovarian cancer and 8,900 control women from 12 U.S. studies, reported an association between fertility drug use and invasive ovarian cancer.[28] The use of fertility drugs was associated with an increased risk of ovarian cancer, primarily in women who did not have a subsequent pregnancy. Two case-control studies published subsequent to the collaborative analysis did not find an association between fertility drug use and risk of ovarian cancer.[29,30]

A retrospective cohort study of women evaluated for infertility observed an increased risk of invasive or borderline malignant ovarian tumors associated with prolonged use of clomiphene.[31] Another retrospective cohort of more than 12,000 women evaluated for infertility found an increased risk of ovarian cancer compared with the general population (standardized incidence ratio 1.98; 95% CI, 1.4–2.6). There was no excess risk with the use of clomiphene or gonadotropins. Although the risks of ovarian cancer were slightly higher among women with 15 or more years from first exposure, the number of exposed cases were small (five exposed cases and three exposed cases, respectively) and observed rate ratios were not statistically significant.

Several other cohort studies of women undergoing infertility treatment have not observed an excess risk of ovarian cancer.[32,33,34] In one study, women with unexplained infertility who were not exposed to fertility drugs had an excess risk of ovarian and uterine cancers.[34]

Talc exposure

A cohort study among nurses did not observe a risk of ovarian cancer associated with perineal talc use (RR = 1.09; 95% CI, 0.86–1.37).[35] A meta-analysis of 16 studies observed an increased risk with the use of talc (RR = 1.33; 95% CI, 1.16–1.45); however, there was no evidence of a dose response.

Height, weight, and dietary factors

Obesity is associated with an increased mortality from ovarian cancer.[36] In cohort studies, height and body mass index (BMI),[37,38] including high BMI during adolescence,[38] were associated with an increased risk of ovarian cancer, suggesting a role for diet and nutrition during the adolescent period.

Associations with specific dietary factors and ovarian cancer are not consistent among observational studies.[39,40,41,42,43,44,45,46,47]

The reduction in risk of ovarian cancer associated with oral-contraceptive use. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. N Engl J Med 316 (11): 650-5, 1987.

Changes to This Summary (02 / 28 / 2014)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Significance

Updated statistics with estimated new cases and deaths for 2014 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about ovarian cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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